TY - JOUR
T1 - Function of ceramide transfer protein for biogenesis and sphingolipid composition of extracellular vesicles
AU - Crivelli, Simone M.
AU - Giovagnoni, Caterina
AU - Zhu, Zhihui
AU - Tripathi, Priyanka
AU - Elsherbini, Ahmed
AU - Quadri, Zainuddin
AU - Pu, Jian
AU - Zhang, Liping
AU - Ferko, Branislav
AU - Berkes, Dusan
AU - Spassieva, Stefka D.
AU - Martinez-Martinez, Pilar
AU - Bieberich, Erhard
N1 - Publisher Copyright:
© 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.
PY - 2022/6
Y1 - 2022/6
N2 - The formation of extracellular vesicles (EVs) is induced by the sphingolipid ceramide. How this pathway is regulated is not entirely understood. Here, we report that the ceramide transport protein (CERT) mediates a non-vesicular transport of ceramide between the endoplasmic reticulum (ER) and the multivesicular endosome at contact sites. The process depends on the interaction of CERT's PH domain with PI4P generated by PI4KIIα at endosomes. Furthermore, a complex is formed between the START domain of CERT, which carries ceramide, and the Tsg101 protein, which is part of the endosomal sorting complex required for transport (ESCRT-I). Inhibition of ceramide biosynthesis reduces CERT-Tsg101 complex formation. Overexpression of CERT increases EV secretion while its inhibition reduces EV formation and the concentration of ceramides and sphingomyelins in EVs. In conclusion, we discovered a function of CERT in regulating the sphingolipid composition and biogenesis of EVs, which links ceramide to the ESCRT-dependent pathway.
AB - The formation of extracellular vesicles (EVs) is induced by the sphingolipid ceramide. How this pathway is regulated is not entirely understood. Here, we report that the ceramide transport protein (CERT) mediates a non-vesicular transport of ceramide between the endoplasmic reticulum (ER) and the multivesicular endosome at contact sites. The process depends on the interaction of CERT's PH domain with PI4P generated by PI4KIIα at endosomes. Furthermore, a complex is formed between the START domain of CERT, which carries ceramide, and the Tsg101 protein, which is part of the endosomal sorting complex required for transport (ESCRT-I). Inhibition of ceramide biosynthesis reduces CERT-Tsg101 complex formation. Overexpression of CERT increases EV secretion while its inhibition reduces EV formation and the concentration of ceramides and sphingomyelins in EVs. In conclusion, we discovered a function of CERT in regulating the sphingolipid composition and biogenesis of EVs, which links ceramide to the ESCRT-dependent pathway.
KW - AlphaFold2
KW - CERT
KW - ER-endosome contact sites
KW - HPA-12
KW - NC03
KW - PI4KIIIβ
KW - PI4KIIIβ-IN-10
KW - PI4KIIα
KW - PI4P
KW - Tsg101
KW - ceramide
KW - extracellular vesicles
KW - sphingomyelin
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UR - http://www.scopus.com/inward/citedby.url?scp=85131165477&partnerID=8YFLogxK
U2 - 10.1002/jev2.12233
DO - 10.1002/jev2.12233
M3 - Article
C2 - 35642450
AN - SCOPUS:85131165477
VL - 11
JO - Journal of Extracellular Vesicles
JF - Journal of Extracellular Vesicles
IS - 6
M1 - e12233
ER -